p53 is known as an important factor for inhibiting canceration of cells. p53 is a transcription factor that induces the expression of genes involved in the cell cycle and cellular apoptosis in response to various stresses. p53 is thought to inhibit canceration of cells by a transcription regulating function thereof. In fact, deletion or mutation of the p53 gene is observed in about half of human cancer cases.
Meanwhile, overexpression of murine double minute 2 (MDM2), a type of E3 ubiquitin ligase, is known as a factor for canceration of cells that are cancerated in spite of the presence of normal p53. MDM2 is a protein whose expression is induced by p53. MDM2 negatively regulates p53 by binding to the transcription activity domain of p53 to decrease the transcription activity of p53, exporting p53 out of the nucleus, and mediating degradation of p53 by acting as an ubiquitination ligase against p53. Therefore, it is thought that inactivation of functions of and degradation of p53 are promoted in cells in which MDM2 is overexpressed, resulting in canceration (Non Patent Document 1).
Paying attention to such functions of MDM2, many approaches have been attempted using substances that inhibit the suppression of p53 functions by MDM2 as candidate anti-tumor agents. Examples of MDM2 inhibitors targeting the MDM2-p53 binding site have been reported, which include spirooxindole derivatives (Patent Documents 1 to 15 and Non Patent Documents 1 to 3), indole derivatives (Patent Document 16), pyrrolidine-2-carboxamide derivatives (Patent Document 17), pyrrolidinone derivatives (Patent Document 18), isoindolinone derivatives (Patent Document 19 and Non Patent Document 4) and dispiropyrrolidine compounds (Patent Document 20).
Bruton's tyrosine kinase (BTK) is an important signaling enzyme that belongs to the Tec family of non-receptor tyrosine kinases and is expressed in all hematopoietic cells except for T lymphocytes and natural killer cells (Non Patent Document 5). BTK plays an essential role in the B cell signaling pathway, which links cell surface B cell receptor (BCR) stimuli to downstream intracellular response. BTK is an important regulatory factor for the development, activation, signal transduction, and survival of B cells.
Ibrutinib (PCI-32765) is a small molecule compound having a BTK inhibitory effect and is reportedly effective for B cell tumors and autoimmune diseases (Patent Documents 21 and 22 and Non Patent Documents 6 and 7). In Europe and the U.S., ibrutinib is used as an anti-tumor drug for mantle cell lymphoma (MCL) and chronic lymphatic leukemia (CLL) as indications and is also under development for diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM) as indications (Non Patent Documents 7 and 8).